Investigating G-protein coupled receptors (GPCRs) as biomarkers of aggressive

尤文肉瘤家族肿瘤（EFT）是高度恶性的骨和软组织肿瘤，主要影响 儿童、青少年和年轻人。尽管采取了积极的地方控制措施， 化疗，超过四分之一的局部肿瘤患者和几乎所有的转移性肿瘤患者 疾病在最初的临床缓解后会在远处复发。不幸的是， 患者的情况令人沮丧，迫切需要新的治疗方法。最大的障碍之一 改善EFT患者的预后和生活质量的关键是我们无法预测谁有EFT的风险。 转移复发，并有效地识别和靶向该过程的基础机制。的 本提案中概述的研究旨在填补我们知识中的这些关键空白。 我们的总体目标是通过预防转移性复发来改善EFT患者的结局。为了 为达致这个目标，我们会致力达致三个具体目标。首先，我们将使用细胞系研究来评估 CXCR 4阳性EFT细胞在介导EFT转移中的作用。我们还将确定是否入侵 CXCR 4下游的蛋白质由RhoA介导并依赖于RhoA。其次，我们将测试小分子 RhoA/MKL转录轴的抑制剂进行体外、离体和体内试验，以评估其作为新的 预防EFT转移的药物。第三，我们将使用回顾性和前瞻性收集的 EFT样本验证G蛋白偶联受体的表达是否可用于预测高风险 新诊断的患者。证明CXCR 4、CXCR 7和/或LGR 5表达可以是 用于识别转移性复发高风险患者将允许将患者分类为临床风险 类别反过来，这将允许治疗分层和识别应该接受治疗的患者。 包括在未来旨在预防高危患者复发的试验中。

Ewing sarcoma family tumors (EFT) are highly malignant bone and soft tissue tumors that primarily affect children, adolescents and young adults. Despite aggressive local control measures and systemic chemotherapy, over a quarter of patients with localized tumors and nearly all patients with metastatic disease will relapse at distant sites following initial clinical remission. Unfortunately, the outlook for these patients is dismal and novel approaches to therapy are desperately needed. One ofthe biggest impediments to improving outcomes and quality of life for patients with EFT is our inability to predict who is at risk for metastatic relapse and to effectively identify and target the mechanisms that underlie this process. The studies outlined in this proposal aim to address these critical gaps in our knowledge. It is our overall goal to improve outcomes for patients with EFT by preventing metastatic relapse. In an effort to achieve this goal we will address three specific aims. First, we will use studies of cell lines to evaluate the role of CXCR4 positive EFT cells in mediating EFT metastasis. We will also determine if invasion downstream of CXCR4 is mediated by and dependent on RhoA. Second, we will test small molecule inhibitors of the RhoA/MKL transcriptional axis in vitro, ex vivo and in vivo to evaluate their efficacy as novel agents forthe prevention of EFT metastasis. Third, we will use retrospectively and prospectively collected EFT samples to validate whether expression of G-protein coupled receptors can be used to predict high-risk disease in newly diagnosed patients. Demonstration that CXCR4, CXCR7 and/or LGR5 expression can be used to identify patients at high risk of metastatic relapse will allow classification of patients into clinical risk categories. In turn, this will allow for treatment stratification and identification of patients who should be included in future trials that are designed to prevent relapse in high-risk patients.